Cataract 17, Multiple Types (CTRCT17) via the CRYBB1 Gene

Cataract 17 (CTRCT17) is a common congenital, bilateral, progressive, nuclear, pulverulent, sutural vision disorder that causes blindness in children (Mackay et al. 2002). It is characterized by the development of blurred and dimmed vision resulting from clouding of the lens (opacification) due to changes in its microarchitecture (Kumar et al. 2013). This particular damage to the lens induces light to scatter as well as proteins to aggregate, thereby resulting in loss of transparency (Hejtmancik 2008). Intrafamilial variability in the morphology and location within the lens commonly occurs in CTRCT17 (Yang et al. 2008). The incidence of congenital cataract has been estimated to be roughly 2 per 10,000 live births (Wirth et al. 2002; Yi et al. 2011). Perinatal ocular examination in newborns via red reflex examination is generally conducted using an ophthalmoscope (American Academy of Pediatrics 2002), whereas young children are assessed by slit-lamp microscopy (Li et al. 2013). Congenital cataract is usually treated by surgery and early primary intraocular lens implantation during the first year of life (Ventura et al. 2013). CTRCT17 has been strongly associated with microcornea (Willoughby et al. 2005).

CTRCT17 is an autosomal dominant vision disorder that is caused by pathogenic sequence variants in the crystallin, beta-B1 (CRYBB1) gene, which is located on chromosome 22q12.1 (Mackay et al. 2002). The CRYBB1 gene consists of five coding exons that encode a 252-amino acid structural protein called beta-crystallin B1, which is expressed in the lens tissue and plays an important structural role in the maintenance of lens transparency and refractive index (David et al. 1996). The CRYBB1 protein has a significantly longer N-terminal extension compared to the other two beta-crystallins, namely CRYBB2 and CRYBB3, thereby allowing the formation of higher molecular weight protein aggregates (Den Dunnen et al. 1986; Ajaz et al. 1997). Pathogenic sequence variants in the CRYBB1 gene significantly reduce the stability of the beta-crystallin B1 monomer via deamidation, thus disrupting the formation of hetero-oligomers and protein folding, which are critical for lens transparency (Harms et al. 2004; Wang et al. 2010; Wang et al. 2013). To date, a total of over 10 pathogenic CRYBB1 sequence variants have been reported, which are mostly missense and a few chain terminations (nonsense and frame shift) (Human Gene Mutation Database). The autosomal recessive form of CTRCT17 less frequency occurs and involves the abrogation of the N terminal region, thus leading to nonsense-mediated decay and ultimately no protein product (Cohen et al. 2007; Meyer et al. 2009).

The clinical sensitivity of this test may range up to 18%. In China, none of the 25 families with congenital cataracts showed pathogenic sequence variants in the CRYBB1 gene (Sun et al. 2011). In two independent studies in India, none of the 60 south Indian families with inherited pediatric cataract (Devi et al. 2008) and 8% (8/100) of congenital cataract cases (Kumar et al. 2013) showed disease-causing CRYBB1 sequence variants. In the United States, 4.3% (1/23) of families with autosomal dominant cataract tested positive for causative CRYBB1 sequence variants (Reis et al. 2013). In Saudi Arabia, 18% (7/38) of pediatric cataract patients harbored pathogenic sequence variants in the CRYBB1 gene (Aldahmesh et al. 2012).

This test provides full coverage of all coding exons of the CRYBB1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).